Immune responses to gene therapy vectors: influence on vector function and effector mechanisms
Immune responses to gene therapy vectors: influence on vector function and effector mechanisms
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DOI：
10.1038/sj.gt.3302364
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发表时间：
2004-10-01
期刊：
影响因子：
5.1
通讯作者：
Boissier, MC
中科院分区：
文献类型：
--
作者：
Bessis, N;GarciaCozar, FJ;Boissier, MC
避开对病媒的免疫反应是所有病媒类型的主要挑战。病毒载体最有可能引起免疫反应，尤其是那些在机体内表达免疫原性表位的病毒载体，如腺病毒和AAV。载体转移后发生的第一个免疫反应来自先天免疫系统，主要是在给药部位周围快速（几小时）分泌炎症细胞因子和趋化因子。腺病毒载体的反应高，而AAV载体的反应几乎为零。值得注意的是，由于CpG刺激胰岛，质粒DNA载体也通过刺激白细胞上的TLR受体来刺激先天免疫。导致抗体产生和T淋巴细胞激活的特异性免疫反应也会在载体引入后的几天内发生。衣壳抗原主要负责对腺病毒的特异性免疫，也参与对AAV的反应。然而，仅在前一种情况下，病毒基因编码蛋白也可能具有免疫原性。来自野生型AAV或腺病毒早期感染的预先存在的体液免疫可以阻止基因与相应载体的有效转移。在所有情况下，一些参数如给药途径、剂量或启动子类型已被广泛描述为影响媒介免疫的关键因素。对抗媒介诱导免疫的策略可以来自免疫学领域，因为耐受诱导或免疫抑制是可能的。对载体结构的改变也被广泛应用于规避免疫系统，从而提高基因转移的效率和安全性。
Circumventing the immune response to the vector is a major challenge with all vector types. Viral vectors are the most likely to induce an immune response, especially those, like adenovirus and AAV, which express immunogenic epitopes within the organism. The first immune response occurring after vector transfer emerges from the innate immune system, mainly consisting in a rapid (few hours) inflammatory cytokines and chemokines secretion around the administration site. This reaction is high with adenoviral vectors and almost null with AAV. It is noteworthy that plasmid DNA vectors, because of CpG stimulatory islets, also stimulate the innate immunity via the stimulation of TLR receptors on leukocytes. Specific immune response leading to antibodies production and T lymphocytes activation also occurs within a few days after vector introduction. Capsid antigens are mostly responsible for specific immunity toward adenoviruses, and are also involved in the response against AAV. In the former case only, however, viral gene-encoded proteins can also be immunogenic. The pre-existing humoral immunity coming from early infections with wild-type AAV or adenovirus can prevent efficient gene transfer with the corresponding vectors. In all cases, some parameters like route of administration, dose, or promoter type have been extensively described as critical factors influencing vector immunity. Strategies to fight against vector-induced immunity can come from the immunology field, since tolerance induction or immunosuppression are a possibility. Alterations to vector structure have also been extensively performed to circumvent the immune system and thus enhance gene transfer efficiency and safety.